Clinical use of aromatase inhibitors in the treatment of advanced breast cancer.

The aim of endocrine therapy is to reduce the estrogenic stimulus for tumour growth. After failure of tamoxifen--the standard "first-line" hormonotherapy for advanced breast cancer (ABC)--the most frequently prescribed endocrine therapies are progestins and aromatase inhibitors (AIs) ("second-line" hormonotherapy). Estrogen deprivation through AIs provides effective treatment of hormone-dependent ABC in postmenopausal (PMP) women. Over the past few years, the goals of our research programme were to develop more potent, more selective and better tolerated AIs than our first AI, aminoglutethimide (AG). Lentaron (4-hydroxyandrostenedione, formestane), a highly selective steroidal compound was the first of the new AIs to be used in clinical trials. It is a substrate analogue, administered as an i.m. injection every 2 weeks. It is effective in the treatment of ABC with an objective response rate (ORR) similar to tamoxifen and megestrol acetate (MA) and is generally well tolerated; rare instances of injection site reactions have been reported. Afema (fadrozole HCl), a non-steroidal AI is active orally, and effectively suppresses estrogen levels in PMP women, but it is not completely selective for aromatase when administered at higher than therapeutic doses. At the therapeutic dose of 1 mg twice a day it has an anti-tumour efficacy similar to MA, a good tolerability and no clinically relevant effects on other hormones of the endocrine system. Letrozole is the fourth of our AIs in clinical development. It is a non-steroidal, achiral, orally active, potent and highly selective competitive AI. Clinical endocrine studies have shown that the dose of 0.5 mg a day is the lowest dose achieving maximum estrogen suppression. Over a wide dose range, a lack of clinically relevant effects on other hormones of the endocrine system has confirmed its high selectivity. In four phase Ib/IIa studies in PMP patients with ABC who failed previous therapy, letrozole produced ORRs of 9, 31, 33 and 36%. One phase IIb/III study has been completed and two others are ongoing, comparing two doses of letrozole with MA or AG to confirm the anti-tumour efficacy of letrozole in the treatment of ABC in PMP women after treatment with anti-estrogens. Preliminary results from the completed trial show that letrozole 2.5 mg is superior to 0.5 mg in terms of ORR, time to progression and time to treatment failure, and is superior to the standard dose of MA in terms of ORR and tolerability. Therefore letrozole 2.5 mg can be recommended as a first choice for the treatment of PMP patients with hormone receptor-positive or unknown ABC after anti-estrogen therapy.

A randomized, double-blind, comparative trial of a new oral combination of artemether and benflumetol (CGP 56697) with mefloquine in the treatment of acute Plasmodium falciparum malaria in Thailand.

CGP 56697, a new oral fixed combination of artemether and benflumetol, was tested in a double-blinded, randomized trial in 252 adult patients treated either with CGP 56697 (4 x 4 tablets each containing 20 mg of artemether and 120 mg of benflumetol, given at 0, 8, 24, and 48 hr), or with mefloquine (three tablets of 250 mg at initial diagnosis, followed by two tablets of 250 mg at 8 hr). Baseline data of the two groups were comparable. The 28-day cure rate with CGP 56697 was lower than with mefloquine (69.3% versus 82.4%; P = 0.002). However, CGP 56697 was more effective than mefloquine in parasite clearance time (43 hr versus 66 hr; P < 0.001) fever clearance time (32 hr versus 54 hr; P < 0.005), and gametocyte clearance time (152 hr versus 331 hr; P < 0.001). This study revealed that CGP 56697 is effective against multidrug-resistant Plasmodium falciparum malaria in Thailand, but higher doses will probably be needed to improve the cure rate.

A randomized controlled trial of artemether/benflumetol, a new antimalarial and pyrimethamine/sulfadoxine in the treatment of uncomplicated falciparum malaria in African children.

We report here the results of a randomized double blind trial comparing coartemether (CGP56697), a combination of artemether and benflumetol, with pyrimethamine/sulfadoxine (P/S). Two hundred eighty-seven children 1-5 years of age with uncomplicated falciparum malaria were enrolled at two centers in The Gambia between July 1996 and December 1996. Following treatment, children were visited at home every 24 hr until a blood film free of asexual parasites was obtained. Genotyping of parasites was used to distinguish recrudescence from new infections. Three days after the start of treatment, 133 (100%) of the CGP56697-treated children compared with 128 (93.4%) of children treated with P/S had cleared their parasites (P = 0.003). The day 15 cure rate was 93.3% for CGP56697 and 97.7% for P/S (P = 0.13). Within the third and fourth week after initiation of therapy, 20 children treated with CGP56697 and one of the P/S-treated children returned with second malaria episodes (P < 0.0001). Genotyping suggested that the majority (19 of 23 [82.6%]) of these second episodes were due to new infections, supporting the World Health Organization recommendation that longer follow-up is not relevant for the assessment of drug efficacy. At the two-week follow-up, 28.9% of the P/S treated children but none of the CGP56697-treated children carried gametocytes (P < 0.0001). This study showed that CGP56697 is safe in African children with acute uncomplicated falciparum malaria, clears parasites more rapidly than P/S, and results in fewer gametocyte carriers. More frequent new infections within the third and fourth week following treatment with CGP56697 than treatment with P/S are likely to be due to the short prophylactic effect of CGP56697.

Hyperglycemia alone does not inhibit secretin-induced pancreatic bicarbonate secretion.

Administration of exogenous insulin (INS) inhibits secretin-stimulated pancreatic bicarbonate (HCO3) output via a dose-dependent, neurally mediated mechanism. To determine whether this effect was due to systemic hyperinsulinemia or to reduced endogenous insulin production, we examined the effect of hyperglycemia on secretin-stimulated pancreatic secretion. Chronic pancreatic fistulae were created in six dogs. After 30 minutes of equilibration, a computer-assisted hyperglycemic clamp protocol was used to maintain glucose (GLU) levels 100 or 150 mg/dL above basal in clamp animals; control animals received volume- and rate-matched infusions of 0.9% saline. One hour after beginning the clamp period, intravenous secretin dose-response (16-125 ng/kg/h) was begun, doubling the dose every half hour. Unstimulated (0-30 minutes) HCO3, GLU, and INS levels did not differ between groups. INS and GLU levels in clamp animals were significantly elevated during clamp (30-90 minutes) and stimulated (90-210 minutes) periods. For the same periods, HCO3 secretion was not significantly changed despite profound hyperinsulinemia. We conclude that systemic hyperinsulinemia alone does not inhibit secretin-stimulated HCO3 output. Since exogenous INS exerts feedback regulation on the pancreas, we propose that suppression of endogenous INS secretion mediates the previously reported inhibitory response.

A television scanner for the ultracentrifuge. II. Multiple cell operation.

The "Optical Multichannel Analyzer" (OMA) is a commercially available instrument that with the absorption optical system of the ultracentrifuge, provides an entire 500 channel intensity profile of a cell in real time. With its own analog-todigital converter, the OMA integrates a selectable number of 32.8 msec scans to provide a time-averaged image in digital form. This paper describes an interface-controller for operation of the OMA with single- and double-sector cells in multi-cell rotors, simulating double-beam measurement required for absorbance determinations. The desired sector is selected by "gating" the intensifier stage of a "Silicon Intensified Target" vidicon (SIT) used as the light detector. The cell location in the rotor and the position of the gate relative to the cell centerline is obtained from a phase-locked loop circuit which divides each rotation of the rotor into 3600 parts independent of rotor speed. (This circuit employed with photo-multiplier scanners would select the gate position for integration of photomultiplier pulses.) From examination of appropriate signals with an oscilloscope, it was verified that gate positions and widths are located with an accuracy of 0.1degree or better and with a precision of +/- 0.1 mus. The light intensity profile for any desired cell can be examined in "real time", even during acceleration of the rotor. Additional circuits employing a 10 MHz crystal clock 1) control the automatic collection of data for all sectors in multicell rotors at digitally selected time intervals, 2) display the rotor speed, and 3) indicate the elapsed time of the experiment. Constructed but not tested are additional circuits for pulsing a laser into the absorption or Rayleigh optical system. The accuracy of the pulsed SIT has been demonstrated by measurement of absorbances of solutions and also by sedimentation equilibrium experiments with myoglobin. The estimated error is 0.003 for absorbances ranging from 0 to 1. The interface-controller operates extremely well, but problems related to the pulsed SIT (optimum gate position relative to the sector opening shape of high-voltage pulse, slight pincushion distortion) require more work.

Phase II trial in China of a new, rapidly-acting and effective oral antimalarial, CGP 56697, for the treatment of Plasmodium falciparum malaria.

One hundred and two Chinese out-patients with naturally acquired, previously untreated, falciparum malaria were selected to evaluate the efficacy of a new combination anti-malaria therapy, CGP 56697 (artemether plus benflumetol). In this open non-comparative trial each patient received a combination of 80 mg artemether and 480 mg benflumetol given orally at 0, 8, 24 and 48 hours (total: 320 mg artemether, 1,920 mg benflumetol). Patients were kept for 28 days in a transmission-free hospital in an area with chloroquine resistant falciparum malaria to prevent reinfection and to aid diagnosis of recrudescence. Progress and possible adverse effects were monitored by blood film parasitology, blood biochemistry assays, urinalysis, ECG and X-ray. Ninety-eight of the 102 patients were shown to be free of infection at 28 days, a 96.1% cure rate. Parasite reduction at 24 hours was 99.4%. Time to effect complete parasite clearance ranged from 24 to 54 hours (median 30 hours). Time for fever clearance ranged from 6 to 78 hours (median 18 hours). Recrudescence was low (3.9%). No significant adverse side-effects were encountered. It is concluded that CGP 56697, a combination anti-malaria therapy of artemether with benflumetol, offered a rapid and highly effective treatment for acute uncomplicated falciparum malaria in an area of chloroquine-resistant malaria in China.

Increasing membrane-bound MCSF does not enhance OPGL-driven osteoclastogenesis from marrow cells.

Macrophage colony-stimulating factor (MCSF) and osteoprotegerin ligand (OPGL), both produced by osteoblasts/stromal cells, are essential factors for osteoclastogenesis. Whether local MCSF levels regulate the amount of osteoclast formation is unclear. Two culture systems, ST-2 and Chinese hamster ovary-membrane-bound MCSF (CHO-mMCSF)-Tet-OFF cells, were used to study the role of mMCSF in osteoclast formation. Cells from bone marrow (BMM) or spleen were cultured with soluble OPGL on glutaraldehyde-fixed cell layers; osteoclasts formed after 7 days. Osteoclast number was proportional to the amount of soluble OPGL added. In contrast, varying mMCSF levels in the ST-2 or CHO-mMCSF-Tet-OFF cell layers, respectively by variable plating or by addition of doxycycline, did not affect BMM osteoclastogenesis: 20-450 U of mMCSF per well generated similar osteoclast numbers. In contrast, spleen cells were resistant to mMCSF: osteoclastogenesis required > or = 250 U per well and further increased as mMCSF rose higher. Our results demonstrate that osteoclast formation in the local bone environment is dominated by OPGL. Increasing mMCSF above basal levels does not further enhance osteoclast formation from BMMs, indicating that mMCSF does not play a dominant regulatory role in the bone marrow.

Bilateral carcinoma of the breast.

Among the 911 cases of carcinoma of the breast treated between 1969 and 1978 there were 39 cases of bilateral primary cancer. Of these, 17 were synchronous tumours defined as cancers diagnosed and treated during the same primary hospital admission. The remaining 22 patients had tumours that were diagnosed separately (metachronous tumours), with a mean time interval of 5 years and 8 months between presentation of first and second primaries (range 6 months to 20 years). Of the metachronous tumours, 20 had presented within 7 years of the diagnosis of the first primary (2.2 per cent of all patients). The patients with synchronous disease fared badly, but patients in the metachronous group had a good prognosis. This is due, at least in part, to the inherent selection of patients in the metachronous group who have to survive the first primary tumour in order to develop the second. However, careful follow-up after the first primary may also account for the relatively good prognosis of this group. We therefore recommend continuing regular out-patient follow-up, with careful examination of the second breast, for all patients having undergone treatment for cancer of the breast.

Randomized comparison of artemether-benflumetol and artesunate-mefloquine in treatment of multidrug-resistant falciparum malaria.

An open, randomized comparison of artemether-benflumetol (CGP 56 697; Novartis) with artesunate-mefloquine was conducted in 617 patients with acute uncomplicated multidrug-resistant falciparum malaria on the western border of Thailand. Both treatments rapidly and reliably cleared fever and parasitemia, and there was no significant difference in the initial therapeutic response parameters. Parasite genotyping was used to distinguish recrudescences from new infections. The 63-day cure rate for artesunate-mefloquine (94%) was significantly higher than the cure rate for artemether-benflumetol (81%) (P < 0.001). Both regimens were well tolerated. Nausea, vomiting, dizziness, sleep disorders, and other neurological side effects were between two and four times more common in the artesunate-mefloquine group than in the artemether-benflumetol group (P < 0.001). Artemether-benflumetol is effective and very well tolerated in the treatment of multidrug-resistant falciparum malaria. A higher dose than that used in the present study may improve efficacy.

Treatment of African children with uncomplicated falciparum malaria with a new antimalarial drug, CGP 56697.

New antimalarial drugs are urgently needed. The use of short courses of the new antimalarial drug artemether as monotherapy has been limited by secondary malaria episodes following parasite clearance. Therefore, a new antimalarial drug, CGP 56697, has been developed, which combines artemether with a longer-acting antimalarial agent, benflumetol. A safety trial was undertaken in 60 Gambian children 1-6 years old with uncomplicated Plasmodium falciparum malaria. All children treated with CGP 56697 cleared their parasites 72 h after the start of treatment. No neurologic, cardiac, or other adverse reactions were observed. Second episodes of falciparum malaria were recorded in 16 (27%) of the children. Second infections were more frequent during the rainy season than during the dry season. Molecular epidemiologic studies suggested that 12 of the 14 second episodes of malaria in children treated with CGP 56697 were due to new infections. CGP 56697 proved to be a safe and effective antimalarial drug in African children.

Efficacy and safety of CGP 56697 (artemether and benflumetol) compared with chloroquine to treat acute falciparum malaria in Tanzanian children aged 1-5 years.

A randomized, open trial involving 260 Tanzanian children, aged 1-5 years, with acute Plasmodium falciparum malaria was conducted to evaluate the efficacy of the combination antimalarial CGP 56697 (artemether and benflumetol), and to compare it with chloroquine, the standard drug used for malaria treatment in the Kilombero area. Children who had received rescue medication within the first 48 h or had a negative slide at the same time were excluded. Seven-day parasitological cure rates were 94% (95% CI 88-97.5) for CGP 56697 and 35.4% (95% CI 25.9-45.8) for chloroquine. Using the same definition, the 14-day parasitological cure rates were 86.4% (95% CI 78.5-92.2) for CGP 56697 and 10.3% (95% CI 5.1-18.1) for chloroquine. Gametocytes were more effectively suppressed by CGP 56697 than by chloroquine. There were no major adverse events with either drug. CGP 56697 is highly efficacious against P. falciparum in this area of Tanzania. The study contributes to the discussion on treatment strategies, particularly whether chloroquine may still fulfil its role as first-line drug in an area of high malaria transmission and very high levels of chloroquine resistance.